1odc



STRUCTURE OF ACETYLCHOLINESTERASE (E.C. 3.1.1.7) COMPLEXED WITH BIS-TACRINE MOLECULES AT 2.2 &Aring; RESOLUTION (see also AChE bivalent inhibitors)

 2d and 2f are bis(n)-tacrine derivatives with n=5 and 7 (number of carbons in the linkers), respectively. These compounds are more potent and selective AChE inhibitors than tacrine alone. The binding of the tacrine moiety of 2d at the TcAChE catalytic anionic site (CAS) is similar to that of tacrine alone (1acj). The second tacrine moiety of 2d interacts with the peripheral anionic site (PAS) near Trp279. The interaction of 2d at the CAS increases the distance between Ser200 Oγ and H440 Nε2 atoms, and, therefore, disrupts the catalytic triad (Ser200, H220, E327) as seen in the native structure (2ace). This binding results in major structural changes in the Val281-Ser291 loop causing a significant change in the surface of the active-site gorge in comparison to the native structure (2ace). The tacrine moiety of 2f (heptylene-linked bis-tacrine, 2ckm) at the CAS,  adopts similar conformation as tacrine alone and the tacrine moiety of the 2d. The second tacrine moiety of the 2f interacts with the PAS near Trp279, in a similar fashion to 2d. The binding of 2f does not cause significant structural changes in the TcAChE upon forming the complex in comparison to the native TcAChE structure. Comparison of the 2d and 2f reveals different contacts between the tacrine moieties of these compounds and  TcAChE at the PAS. There are two additional structures of complexes of TcAChE with tacrine-containing AChE inhibitors: compounds 6 (1ut6) and <scene name='2cmf/Comparison/9'>7 (1odc). The tacrine moieties of these compounds display similar conformations and interactions with CAS as tacrine alone, 2d and 2f. Both inhibitors 6 and 7 are spanning the <scene name='2cmf/Comparison/10'>active-site gorge from the CAS up to the PAS, but since compound 7 lacks the second tacrine moiety, Trp279 adopts a different conformation in this complex structure. In the three structures: native (cyan), TcAChE-cmp 6 complex (white), and TcAChE-cmp 7 complex (crimson), except of Trp279, all the other TcAChE active-site gorge residues have similar conformations.

About this Structure
1ODC is a Single protein structure of sequence from Torpedo californica. Full crystallographic information is available from OCA.

Additional Resources
For additional information, see: Alzheimer's Disease

Reference
Complexes of alkylene-linked tacrine dimers with Torpedo californica acetylcholinesterase: Binding of Bis5-tacrine produces a dramatic rearrangement in the active-site gorge., Rydberg EH, Brumshtein B, Greenblatt HM, Wong DM, Shaya D, Williams LD, Carlier PR, Pang YP, Silman I, Sussman JL, J Med Chem. 2006 Sep 7;49(18):5491-500. PMID:16942022

Page seeded by OCA on Sat May 3 03:41:58 2008